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Gene Dosage of 9p21 Affects Risk, Severity of Coronary Artery Disease

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The 9p21 variant has been well linked to heart disease, but researchers are only beginning to untangle how that connection works. In 2007, a group led by the University of Texas Southwestern Medical Center's Jonathan Cohen reported in Science that people who are homozygous for the 9p21 variant — which is common in Asian and Caucasian populations — had a 30 to 40 percent increased risk of developing coronary artery disease than people without the variant. At the same time, a group from DeCode Genetics linked the variant to risk of myocardial infarction, writing in that same issue of Science that it increased risk of heart attack by 1.64 times. But the University of Ottawa's Alexandre Stewart, who collaborated with the Texas group, says they did not know the underlying biology of the association.

"We still didn't know the answer to the question, was this a risk factor for myocardial infarction per se? Or was this a risk factor for coronary artery disease first, and myocardial infarction second?" Stewart says.

Gene dosage of 9p21, Stewart and his colleagues report in the Journal of the American College of Cardiology, predicts the severity of coronary artery disease, but not myocardial infarctions. In a cross-sectional case-case study, they looked at the disease severity — as determined by angiograms — of people with early-onset coronary artery disease coming into their Ottawa clinic and related it to their 9p21 genotype. They then replicated that in an independent, older population of patients.

"To our surprise, the same relationship that we saw in the patients with the early onset symptoms was also observed in the elderly samples," Stewart says. "What this tells us is that it is just [as] much a risk for coronary atherosclerosis in older people as it is in younger people."

In addition, a Chinese group led by Weifeng Shen at the Shanghai Jiaotong University School of Medicine found similar results. They report in Cardiovascular Diabetology that being homozygous for the 9p21 variant is also associated with more severe coronary artery disease in a Han Chinese population. However, the researchers note that the association is not seen in people with diabetes. "That's interesting, suggesting that diabetes can cause more damage, it looks like, than this genetic variant alone," Stewart adds.

Stewart's group is now searching for genes that modify the risk conferred by this locus and others. So far, they have found that the 9p21 region regulates the expression of flanking genes that are important in controlling cell proliferation. "That's part of the story," he says. "The biology is coming slowly."

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